The carboxylic acid functional group plays a cardinal role in the biochemistry of living systems as well as in drug design. A wide variety of endogenous substances, such as amino acids, triglycerides and prostanoids possess the carboxylic acid moiety. Furthermore, this functional group is often part of the pharmacophore of diverse classes of therapeutic agents. Indeed, a large number of carboxylic acid-containing drugs (>450) have been marketed worldwide, including widely used non-steroidal anti-inflammatory agents, antibiotics, anti-coagulants, and cholesterol-lowering statins, among others. The acidity, combined with the ability to establish relatively strong electrostatic interactions and H-bonds, are the reasons this functional group is often a key determinant in drug-target interactions. However, despite the success of carboxylic acid drugs, the presence of a carboxylic acid residue in a drug or a drug candidate can represent a liability. For instance, a reduced ability to passively diffuse across biological membranes may raise a significant challenge, particularly in the context of CNS-drug discovery, where the blood-brain barrier (BBB) can be relatively impermeable to negatively charged carboxylates. Furthermore, idiosyncratic drug toxicities arising from the metabolism of the carboxylic acid (e.g., glucuronidation) have been linked to withdrawals of marketed drugs. Thus, to avoid these and other possible shortcomings, the replacement of the carboxylic acid functional group with a suitable surrogate, or (bio)-isostere, can represent an effective strategy.
The thromboxane A2 prostanoid (TP) receptor is known to be involved in platelet aggregation, as well as vaso- and broncho-constriction. Furthermore, the TP receptor signaling cascade has been implicated in the pathogenesis of Alzheimer's disease and certain forms of cancer. TP receptor antagonists can be therapeutically useful to treat conditions including cardiovascular and respiratory diseases, certain forms of cancer, and neurodegenerative diseases. As such, effective antagonists of the TP receptor are needed.